PROJECT SUMMARY/ABSTRACT: This project is a NIH Mentored Clinical Scientist Research Career Development Award (K08) application for Dr. Eric Allenspach, an Acting Assistant Professor in the Department of Pediatrics at the University of Washington (UW). Dr. Allenspach has completed his clinical training in Pediatric Rheumatology and Immunology and has both a clinical and research interest in the treatment of pediatric autoimmune conditions. Dr. Allenspach's specific research interest is understanding the role of genetic risk factors in regulating the myeloid lineage and the interaction between the innate and adaptive immune responses. His long-term career goal is to establish himself as an independently-funded principle investigator studying these mechanisms in both animal models and directly in primary human cells using basic science and translational approaches. In order to achieve this goal, Dr. Allenspach is requesting the NIH K08 support for additional training and mentorship in the following specific areas: (1) assessment of murine myelopoiesis and technical skills in ex vivo manipulating human myeloid cells; (2) training in laboratory techniques related to gene knockdown and gene editing; (3) additional training in proteomic approaches and big data analysis; (4) NOD murine modeling of spontaneous diabetes. (5) presenting at scientific conferences, career development seminars, and additional classroom-based training relevant to this project; and (6) grantsmanship and laboratory management with a focus on developing an independent research focus with a goal of transitioning to scientific independence. In the present application, Dr. Allenspach proposes studying the biologic role of an identified autoimmune risk variant in the adaptor protein SH2B3 on the development of type 1 diabetes (T1D) and in regulating myelopoiesis. A strong association has been found between a genetic allele (rs3184504) in the SH2B3 gene and T1D. In this proposal, we utilize murine modeling to understand how reduced SH2B3 function affects APCs during T1D development and under environmental stress. The overall goal of the project is to test whether the SH2B3 risk variant alters T1D pathogenesis. These studies will focus on the following areas: In Aim 1, we test does the SH2B3 T1D risk allele alter the inherent function of the myeloid APCs. As monocytes are the precursors to several myeloid effector cells, we test in Aim 2 whether having more precursor monocytes during inflammation lead to increased numbers of progeny including monocyte-derived DCs. In Aim 3, we ask directly whether the rs3184504*T allele modeled in mice contributes to T1D by introducing the genetic change on the NOD mouse background. In this proposal, we will directly assess the functional role for this common risk variant in T1D, and, in parallel, gain new knowledge about monocyte biology relevant to T1D pathogenesis. It is anticipated these studies would provide the publications and preliminary data needed to develop an independent research direction and apply for R01 funding at the end of the career development support.